Camptothecin (“CPT”) is an alkaloid isolated from the Chinese tree Camptotheca acuminate. CPT is a topoisomerase I inhibitor (i.e., deoxyribonucleic acid replication is blocked in cells exposed to CPT) with antineoplastic and antitumor properties. This activity motivated the evaluation of CPT as a chemotherapeutic agent, but development was discontinued when severe and unpredictable dose-limiting toxicities were observed, such as hemorrhagic cystitis in the bladder and diarrhea. Furthermore, direct parenteral administration is limited by CPT's poor solubility.
CPT derivatives and analogs have been similarly disappointing. The carboxylate salt form of CPT is less active and causes severe and unpredictable toxicity. Although two CPT analogs, topotecan (Hycamptin) and irinotecan (CAMPTOSAR®), are approved for clinical use in the United States as anticancer drugs, these analogs are associated with bone marrow suppression and diarrhea. Irinotecan-induced diarrhea can be fatal (Garcia-Carbonero and Supko (2002) Clin. Cancer Res. 8:641-661).
In order to mitigate the toxic effects of CPT while maintaining its therapeutic efficacy, formulations and drug release systems have been developed. WO 2005/023294 describes a drug release system that retains the antitumor activity of CPT while limiting toxicity and increasing solubility and plasma half-life by linking CPT to a polymer backbone containing acetals and/or ketals. This polymer backbone is biodegradable and biocompatible. Acetal and ketal polymers are known to degrade in aqueous solution (Papisov et al., Biomacromolecules (2005) 6: 2659-70, which is hereby incorporated in its entirety by reference). Furthermore, CPT is attached to the polymer via ester and amide linkages which tend to hydrolyze in solution. These characteristics make storage difficult, particularly storage of aqueous solutions of CPT-polymer conjugate.
Thus, there exists a need in the art for a storage stable formulation of CPT-polymer conjugates that retains the antitumor activity of CPT while limiting toxicity and increasing solubility. Injectable lyophilized solution powder needs to be reconstituted in Sterile Water for Injection USP, or Saline for Injection USP, for infusion. Thus, there is a need for formulations that are rapidly dissolved to minimize preparation time in the hospital or clinic pharmacy.